Chemistry of Amino Acids, Heterocycles, Peptides and Proteins

Team F9 - Team leader : M. Amblard (DR, CNRS)

The team carries out researches in four main areas using a strong expertise in peptide chemistry :

(1) The developement of small molecules and peptidomimetics, and study of their pharmalogical activities (Hormone peptides and enzyme substrate analogues, heterocycles and vectors).(2) The design and structural studies of organized oligomers or foldamers.(3) The design of biopolymers and hybrid biomaterials.(4) Methodological development including solid phase synthesis strategies and the design of tools for the analysis of biomolecules.

Join the crew !

Numerous positions are open in the team each year to join our ongoing projects : 2 months-training periods for undergraduates, 6-months Master research projects, PhD fellowships and post-doc positions.Do not hesitate to contact us to candidate to the CNRS researcher’s recruitment examination.E-mail : Muriel Amblard

The Team Amino Acids, Heterocycles, Peptides and Proteins of the IBMM is looking for an Organic Chemist/Medicinal Chemist candidate to participate to a multidisciplinary research project. The project aims at developing alternative and specific therapeutic tools based on foldamer and stapled peptide technologies to inhibit protein-protein interactions that are essential for the activity of a nuclear receptor involved in the resistance of tumor cells and cancer stem cells to chemotherapy.The candidate should have a PhD in chemistry (organic synthesis). Previous experience in peptide science and peptidomimetics, in medicinal chemistry and solid support synthesis will be appreciated but not essential. The candidate should also have experience in purification and characterization of organic molecules using analytical techniques such as LC-MS, HPLC, IR, circular dichroism and NMR.The candidate is expected to be highly motivated, independent, and capable of designing synthetic routes, solving challenging synthetic problems, proposing alternative strategies and write journal articles. In addition, the project being at the interface of chemistry, structural analyses and biology, the candidate should be able to closely collaborate with biophysicists/physicians and biologists. The candidate should be fluent in French and/or in English.

Team permanent members

Research

Ghrelin receptor (GHSR) is a prominent target in biomedicine. Indeed, development of compounds that would modulate the signaling of the ghrelin receptor has been actively pursued by the pharmaceutical industry for treatment of obesity, diabetes or drug/alcohol use disorders. In collaboration with the pharmacology team (J.L. Banères, F13), we try to understand and modulate the different signaling pathways of this receptor through more than 800 analogues of ghrelin. Some of these compounds exhibit various biological activities : antagonist, agonist or inverse agonist. Two molecules are actually in clinical or preclinical trials : compounds JMV 1843 and JMV 2959.Collaboration ghrelin :J.L. Banères (team F13)/Aeterna-Zentaris, Frankfurt, Germany/Pr Paul Wellman, Texas, U.S.A./Pr Antonio Torsello, Pr Vittorio Locatlli, Milano, Italy/Pr Lenka Maletinska, Praga, Czech Republic/ Pr Wolfgang Hauber, Stuttgart, Germany

We also develop peptidic tools based on hormone sequences for therapeutic, imaging or purification purposes in collaboration with Pr Marion de Jong (Rotterdam, The Netherlands) and Pr Thea Maina (Athens, Greece). For example, bombesin analogues were synthesized for theranostic use in prostate and breast cancer.

• Metallo-b-lactamases inhibitors to fight the bacterial resistance to b-lactam antibiotics : The emergence of antibiotic-resistant bacteria represents a growing threat to public health and endangers the effective treatments of infections. In Gram-negative bacteria, resistance to b-lactam antibiotics is commonly mediated by b-lactamases, of which metallo-b-lactamases (MBL) are highly worrying. This needs an urgent response. We identified heterocyclic inhibitors showing an original mode of binding to the di-zinc active site of these enzymes. This project is currently supported by ANR (ANTIMBL, 2014-2018) and associates two specialists in theoretical chemistry (Dorothée Berthomieu, ICGM, Montpellier, and Nohad Gresh, ICT, Paris) and two foreign teams in charge of the biological evaluation (Jean-Denis Docquier, Siena University, Italy, and Moreno Galleni, CIP, Liège, Belgium).

• Inhibitors of HslVU, a proteasome-like complex essential to Leishmania and Trypanosoma parasites : we develop peptides/pseudopeptides able to inhibit the assembly of the complex in collaboration with Olivier Coux (CRBM, Montpellier) for enzyme production and testing, and Pierre Marty and Grégory Michel (C3M, Nice) for evaluation on parasites. Vectorization of the compounds is also considered.

• Inhibitors of SUB-1, a peptidase essential to Plasmodium falciparum, the parasite responsible of Malaria : this project is developed in collaboration with Jean-Christophe Barale (Institut Pasteur) for enzyme production and inhibitor testing, and Arnaud Blondel (Institut Pasteur) for molecular modelling.

• New anticancer agents : Recently, we identified pyrido-imidazodiazepine derivatives particularly active against melanoma and displaying an original mechanism of action. In collaboration with team F16 of IBMM (Pr P. Cuq, Dr L.A. Vincent) and P. Pasero team (IGH, Montpellier), we’re studying this new family of compounds, using both proteomic and transcriptomic approaches. In particular, we are developping a clickable approach to visualize the subcellular localization and to identify the cellular target of these compounds.This project is currently financed by « Ligue contre le cancer » (2017-2019). • Kallikrein inhibitors : Kallikrein peptidases (KLK) are a family of serine proteases which are implicated in many complex proteolytic networks. It is now well-etablished that dysregulation of their activities could generate several pathophysiological disorders, such as neurodegenerative pathologies, metastasis spreading or skin disorders. Based on structure-drug design, we’re developing small inhibitors of KLK7 and KLK6 in collaboration with Pr C. El-Amri (UPMC, Paris).

• Arf-1-Arno protein-protein interaction inhibitors (PP2I) : Cancer invasion by breast cancer metastasis is associated to the high expression of ADP-ribosylation factor 1 (Arf1). Our goal is to inhibit the activation of Arf1 using molecules that interfere with its binding to the Sec7 domain of ARNO. We developed several competitive inhibitors based on an original strategy that merges g-peptide oligomers named ATC and active small compounds (fragment-based drug design). The potential of synthesized molecules is evaluated through an integrative approach via biophysics and structural technics and on breast cancer models in collaboration with M. Pugnière (IRCM, Montpellier), and Y. Teng (Augusta University). • hERG potassium Channel, from expression optimization to structural approach : Using an integrative network of biochemist, chemist and structural biology teams, we developed a research program to solve the 3D structure of the human potassium channel hERG. The main goals of our work is to i) optimize the production of hERG using several expression systems ii) extract and purify a functional protein from membranes based on a free-detergent approach iii) investigate the 3D structure of hERG via the electron microscopy methodology. As this channel is also sensitive to drug binding which can result in drug-induced long QT syndrome of the cardiac function, our study may help to better understand the nature of molecular interactions of drugs and will allow the development of more safety therapeutic compounds. Collaborations : J.L. Banères (team F13, IBMM). V Darcos (team C5, IBMM), P. Bron (CBS, Montpellier), S. Granier (IGF, Montpellier). French Pharmaceutical Company SERVIER.

Our group develop pseudopeptide oligomers constructed from constrained beta-amino acids (collaboration with team F10, Dr M. Calmès), gamma-amino acids or dipeptide mimetics that are able to adopt stable and predictable helical and ribbon conformations. Due to their well-defined secondary structure and their resistance to enzyme degradation, these oligomers are used for different biological applications, in particular for the development of efficient vectors for drug delivery, inhibitors of protein-protein interactions or antimicrobials.CD and NMR data are recorded at the « Laboratoire de Mesures Physiques (LMP, UM) ». FT-IR spectra are recorded at the « Laboratoire Charles Coulomb (L2C, UM) » in collaboration with Pr J.L Bantignies. X-ray measurements and the analysis of the diffraction data are performed in collaboration with Dr C. Didierjean (CRM2, University of Lorraine). Biological applications are currently developped in collaboration with Dr M. Morris (team F13, IBMM) and Dr J.M. Pascussi (IGF, Montpellier). Both constrained oligomers and stapled peptides are developed in these projects, respectively funded by INCA (2014), SATT AxLR, the Labex chemisyst and the SIRIC Montpellier Cancer. Industrial partners : Sanofi-Aventis, Servier.

• Foldamer vectors represent promising alternative tools to cell-penetrating peptides, for the delivery of drugs to cells that remains a major limitation in several therapies. In this field, our group developed a series of dipeptide mimetic oligomers that showed high propensity to deliver biologically relevant cargo to cancer cells. Based on their structure, we designed a novel class of oligomers that allowed a flexible modulation of their physical properties and intracellular trafficking pathways.Collaborations : Dr N. Bettache and Dr M. Garcia (team F14, IBMM), Pr S. Ballet (VUB, Bruxelles).

With their outstanding range of structures, structural and biological activities, peptides are highly attractive molecules to give a tailored function to an existing material but also to design innovative materials with unprecedented properties. Existing approaches to functionalise materials with biomolecules mostly relies on post-modification using conjugation chemistry (e.g. click reactions, activated esters). On the contrary, we envisioned innovative bottom-up approaches based on peptide building-blocks bearing functions for polymerisation or condensation. We investigated organic polymerisation using peptides bearing N-carboxyanhydride (NCA) moieties or lactame rings but also inorganic polymerisation methods, using sol-gel process relying on hydroxysilane-derivatized peptides.Applications are numerous and some of them are currently investigated thought founded programs and collaborations :• The functionalization of medical devices and dressing with wound-healing and/or antibacterial peptides and the design of smart ‘communicant’ dressings using RFID technology.• The synthesis of multi-ligands nanoparticles for cancer treatment and imaging.• The synthesis of polymers for cell targeting and vectorization. • The design of biomimetic hydrogels for cell-based therapies that can be printed as 3D scaffolds.From a fundamental point of view, the self-assembly of hybrid peptides is also studied for the design of new nanostructured materials.

Design and synthesis of heterocycles for therapeutic applications : Heterocycles are common structural units in marketed drugs and in medicinal chemistry due to the central role they play in modern drug design. Indeed, they are useful scaffolds that can be decorated with various substituents in order to modulate lipophilicity, polarity, and hydrogen bonding capacity of molecules. These structural modulations may lead to improved pharmacological, pharmacokinetic, toxicological, and physicochemical properties of drug candidates. In order to find new potential lead compounds for therapeutic applications, we develop methodologies to access and structurally modulate heterocycle scaffolds such as [1,2,4]triazoles, diazepines, thiazoles and triazole-ketopiperazines.